CN103037841A - Intravenous curcumin and derivatives for treatment of neurodegenerative and stress disorders - Google Patents

Intravenous curcumin and derivatives for treatment of neurodegenerative and stress disorders Download PDF

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CN103037841A
CN103037841A CN2011800245041A CN201180024504A CN103037841A CN 103037841 A CN103037841 A CN 103037841A CN 2011800245041 A CN2011800245041 A CN 2011800245041A CN 201180024504 A CN201180024504 A CN 201180024504A CN 103037841 A CN103037841 A CN 103037841A
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curcumin
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L·赫尔森
S·邱
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Signpath Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593—Polyesters, e.g. PLGA or polylactide-co-glycolide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

Liposomal formulations and polymer conjugates of curcumin, curcumin analogues and derivatives thereof for parenteral administration are disclosed herein. The formulations are effective in the treatment of progressive supranuclear palsy, Alzheimer's disease (AD), Parkinson's disease (PD), Tauopathies or stress disorders including Post Traumatic Stress Disorder (PTSD). Curcumin crosses the blood brain barrier, localizes in the hiTppocampus and striata, prevents stress-induced neuronal cell damage, and stimulates neurogenesis and remediation of damaged neural circuits.

Description

The vein curcumin and the derivant that are used for the treatment of nervus retrogression and stress disorder
The invention technical field
The present invention relates generally to control and treat the field of stress-related disorder, and the intravenous formulations that relates more specifically to comprise liposomal curcumin is used for the treatment of the purposes of neurodegenerative disorders and stress disorders, and described stress disorders comprises posttraumatic stress disorder (PTSD).
Background technology
In the situation about not limiting the scope of the invention, its background is described in conjunction with the purposes that the compositions that comprises curcumin and its analog and derivant is used for the treatment of neurological disorder, neurodegenerative disorders and other obstacles.
No. 20080033055 U.S. Patent application (Miller and Mitchell, 2008) relates to realizes 1,7-diaryl-1,6-heptadiene-3,5-diketone, and particularly curcumin and synthetic the improving one's methods of analog thereof.This invention also relates to the purposes of this synthetic product in treatment Alzheimer and other diseases.
No. 20090143433 U.S. Patent application (Hendrix; 2009) disclose that to be used for prevention and treatment nervous system disease and cognitive defect (cognitive deficiencies) be Alzheimer (AD); parkinson disease; amyotrophic lateral sclerosis (amyotrophic lateral sclerosis); the preparation of the dementia of mild cognition impairment (mild cognitive impairment) and other types, described preparation comprises the curcumin for the treatment of effective dose; piperine; table GC (epigallocatechin)-3-gallate (EGCG) and NAC.This combination can cause the approach of nerve defective, degeneration and disease for some or all.
No. 20080213246 U.S. Patent application (Ziff and Ziff, 2008) discloses dietary supplement, compositions and given these supplement and be used for reducing pain, inflammation and stiff method this mammal within a few hours.Described supplement and compositions can comprise the combination of aminoacid, vitamin, medical herbs and enzyme.Said composition/supplement can place capsule form, and when giving mammal, these symptoms be can within about 2 hours, reduce, pain and the inflammation relevant with scratch (normal everyday bumps and bruises) with chronic joint discomfort, chronic low-back pain (chronic low back pain), muscular tone, arthritis, athletic injury, normal daily lump reduced.This new compositions has been shown as at the menstrual symptom (monthly menstrualsymptoms) that reduces per month very effective in (PMS).This new compositions also can be beneficial to other diseases (aliment), and described disease is such as but not limited to osteoarthritis, cardiovascular disease, nervous system disease, Alzheimer and cancer.
Summary of the invention
The invention describes by vein and give curcumin, curcumin analogue, derivant or its combination, compositions and the method for the treatment of later stage progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD) and other nerves and nervus retrogression disease.
In one embodiment, the present invention relates to at experimenter's relief of symptoms and/or treat one or more neurodegenerative diseases, neurological disorder, the compositions of anxiety disorder or its combination, said composition comprises: (i) one or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin in water or the nonaqueous solvent, curcumin analogue, curcumin derivate or its combination in any, and dissolving, be dispersed or suspended in one or more the optional relevant cofactors in this solvent, protein, antibody, analgesic and other pharmaceutically active agents; The water that (ii) is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; (iii) one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.In one aspect, above disclosed described one or more neuropathic conditions of this paper or nervus retrogression disease are selected from: progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease, alzheimer disease, vascular dementia, Pick's disease, Ke-Ya Shi sick (Creutzfeldt-Jacobs disease) and old and feeble.In yet another aspect, described one or more anxiety disorders comprise stress disorders, posttraumatic stress disorder (PTSD), phobia, psychic trauma or its combination.
In yet another aspect; described lipid or phospholipid are selected from: phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.Again aspect another, described compositions through vein, through subcutaneous, through intramuscular or through the intraperitoneal administration.In yet another aspect, the size of described one or more liposomees is about 100nm.One concrete aspect, described compositions is through intravenously administrable.
Another embodiment of the invention discloses and has been used at experimenter's relief of symptoms and/or treats one or more neurodegenerative diseases, neurological disorder, the compositions of anxiety disorder or its combination, said composition comprises: the Biodegradable polymeric conjugate, this conjugate dissolves or is dispersed in the suitable water or nonaqueous solvent, wherein said conjugate comprises the curcumin that is conjugated to one or more polymer, curcumin analogue, curcumin derivate or its combination, described polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO (polydioxanones), polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, the polyalkylene oxalate, the polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination thereof or mixture; With one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.In one aspect, described one or more neuropathic conditions or nervus retrogression disease are selected from: progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease, alzheimer disease, vascular dementia, Pick's disease, Ke-Ya Shi disease and old and feeble.In yet another aspect, described one or more anxiety disorders comprise stress disorders, posttraumatic stress disorder (PTSD), phobia, psychic trauma or its combination.At a related aspect, described compositions is through intravenously administrable and be polylactic acid-glycollic acid (PLGA)-curcumin conjugate.
In another embodiment again, the invention provides at experimenter's relief of symptoms and/or treat the method for one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination, the method comprising the steps of: identification needs relief of symptoms and/or treats the experimenter of one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination; With give one or more pharmaceutical compositions through vein, described pharmaceutical composition comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination of the treatment effective dose in the medium of suitable water or non-water, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.Method described here also comprises the step of the effect of the alleviation of monitoring symptom or neurodegenerative diseases, neurological disorder or both treatments, and the improvement of memory, cognition, study, language, one or more motor skill or its combination of described monitoring by observing the experimenter is carried out; And also comprise the step of effect of monitoring the treatment of the alleviation of symptom or anxiety disorder by the change of observing experimenter's emotion or behavior.At described method related aspect; described liposome comprises lipid or phospholipid wall; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.In yet another aspect, described biodegradable polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, polyalkylene oxalate, polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination or mixture.
In one aspect, described pharmaceutical composition is polylactic acid-glycollic acid (PLGA)-curcumin conjugate.In yet another aspect, described one or more liposomees are of a size of about 100nm.Again aspect another, described treatment effective dose comprises experimenter's body weight of 50nM/kg.In yet another aspect, described pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.In yet another aspect, described pharmaceutically active agent comprises serotonin reuptake inhibitor, Sertraline and paroxetine.
In one embodiment, the present invention relates to for experimenter's relief of symptoms and/or the treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), the compositions of Protein tau disease or posttraumatic stress disorder (PTSD), said composition comprises: one or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin in water or the nonaqueous solvent, curcumin analogue, curcumin derivate or its combination, and dissolving, be dispersed or suspended in one or more the optional relevant cofactors in the solvent, protein, antibody, analgesic and other pharmaceutically active agents; The water that is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; With one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.In one aspect; described lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.In yet another aspect, described one or more liposomees are of a size of about 100nm.In yet another aspect, described compositions is through intravenously administrable.
In another embodiment, the invention provides for experimenter's relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD) through the vein compositions, said composition comprises: with curcumin, curcumin analogue, curcumin derivate and its combination or the trim that biodegradable polylactic acid-glycollic acid (PLGA) copolymer is puted together, wherein said conjugate dissolves or is dispersed in the suitable water or nonaqueous solvent; With one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.
Again another embodiment of the present invention relates to for the method at experimenter's relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD), and the method comprising the steps of: identification needs to alleviate and/or treat the experimenter of progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD); With give one or more pharmaceutical compositions through vein, described pharmaceutical composition wraps in (enclose) one or more spherical liposomees or is conjugated to the curcumin of the treatment effective dose of biodegradable polylactic acid-glycollic acid (PLGA) copolymer, curcumin analogue, curcumin derivate or its combination, wherein said liposome, described conjugate or both dissolvings or be dispersed in the medium of suitable water or non-water.The method of the present invention also comprises the step of the effect of the alleviation of monitoring symptom or treatment, and described monitoring is undertaken by the improvement of experimenter's memory, cognition, study, language, one or more motor skill, emotion, behavior or its combination.In one aspect, described liposome comprises lipid or phospholipid wall.In yet another aspect; described lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.In yet another aspect, the size of described one or more liposomees is about 100nm.Again aspect another, the treatment effective dose comprises experimenter's body weight of 50nM/kg.In one aspect, described pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.In yet another aspect, described one or more pharmaceutically active agents are selected from: serotonin reuptake inhibitor Sertraline, paroxetine, levodopa, carbidopa, benserazide, tolcapone, dopamine agonist bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, MAO inhibitor, selegiline and rasagiline.
In one embodiment, the invention discloses for the compositions at experimenter's relief of symptoms or treatment posttraumatic stress disorder (PTSD), said composition comprises: activating agent, described activating agent comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in water or the nonaqueous solvent, wherein said activating agent wraps in one or more liposomees that comprise lipid or phospholipid wall, perhaps puts together with one or more biodegradable polymer; Dissolve, be dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the solvent; With one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.
Aspect of compositions disclosed above, one or more spherical liposomees or polymer conjugate can be dispersed in the disperse medium, and wherein said disperse medium is the disperse medium of water or non-water.At related aspect; described lipid or phospholipid are selected from: phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine; and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate, and described one or more Biodegradable polymerics are selected from: polyester; polyactide; polyglycolide; polycaprolactone; polyanhydride; polyamide; polyurethane; polyesteramide; PPDO; polyacetals; polyketals; Merlon; poly-orthocarbonic ester; poe; poly phosphate; polyphosphazene; poly butyric ester; poly-hydroxyl valerate; the polyalkylene oxalate; the polyalkylene succinate; poly-(malic acid); poly-(aminoacid); copolymer; terpolymer and combination thereof or mixture.
In yet another aspect, described compositions through vein, through subcutaneous, through intramuscular or through the intraperitoneal administration.One concrete aspect, the size of described one or more liposomees is about 100nm.Again aspect another, described compositions is through intravenously administrable.
In another embodiment, the invention provides for the method at experimenter's relief of symptoms or treatment posttraumatic stress disorder (PTSD), the method comprising the steps of: (i) identification needs the experimenter of relief of symptoms or treatment PTSD; (ii) treat the pharmaceutical composition of effective dose through vein, described pharmaceutical composition comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in the medium of suitable water or non-water, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.
In one aspect, method disclosed above also comprises the step of effect of the treatment of the alleviation of the change monitoring symptom by observing experimenter's emotion or behavior or PTSD.In yet another aspect; described liposome comprises lipid or phospholipid wall; wherein said lipid or phospholipid are selected from: phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.Again aspect another, described biodegradable polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, polyalkylene oxalate, polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination or mixture.
Aspect above-described method concrete, described one or more liposomees are of a size of about 100nm, and described treatment effective dose comprises experimenter's body weight of 50nM/kg.At related aspect, described pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents, wherein said pharmaceutically active agent comprises serotonin reuptake inhibitor Sertraline and paroxetine.
Again aspect another, the present invention relates to for the compositions in experimenter's relief of symptoms or treatment parkinson disease (PD), said composition comprises: (i) one or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin in water or the nonaqueous solvent, curcumin analogue, curcumin derivate or its combination, and dissolving, is dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the solvent; The water that (ii) is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; (iii) one or more optional excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any.In one aspect, the size of described one or more liposomees is about 100nm.In yet another aspect, described compositions is through the passages through which vital energy circulates administration.
The method of in experimenter relief of symptoms or treatment parkinson disease (PD) is disclosed in one embodiment of the invention.Method disclosed herein comprises step: (i) identification needs the experimenter of relief of symptoms or treatment PD; (ii) treat the pharmaceutical composition of effective dose through vein, described pharmaceutical composition comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in the medium of suitable water or non-water, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.In one aspect, the method also comprises the step of effect of monitoring the treatment of the alleviation of symptom or PD by the change of observational language, one or more motor skill and other functions.
In yet another aspect; described liposome comprises lipid or phospholipid wall; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.One concrete aspect, the size of described one or more liposomees is about 100nm.In yet another aspect, described treatment effective dose comprises experimenter's body weight of 50nM/kg.Again aspect another, described pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.Aspect another of method disclosed above, described one or more pharmaceutically active agents are selected from: levodopa, carbidopa, benserazide, tolcapone, dopamine agonist bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, MAO inhibitor, selegiline and rasagiline.
Description of drawings
In order to understand more completely the features and advantages of the present invention, quote detailed description of the present invention and appended figure at this, and wherein:
Fig. 1 is the standard curve of curcumin (CCM).
Detailed Description Of The Invention
Although discussed hereinafter preparation in detail and used different embodiment of the present invention, should be realized that to the invention provides a plurality of enforceable inventive concepts, implement under the specific environment of described inventive concept in can be on a large scale.Specific embodiments discussed herein has only illustrated preparation and has used concrete mode of the present invention, and do not limited the scope of the invention.
For the ease of understanding the present invention, a plurality of terms have been defined hereinafter.The meaning of usually understanding at the those of ordinary skill in the term field related to the present invention of this definition is consistent.Term has no intention only to refer to single entity such as " one ", " a kind of " and " being somebody's turn to do ", but comprises the large class that can be used for the object lesson of explaining.This term is used herein to describes specific embodiments of the present invention, but its use does not limit the present invention, unless in the claims general introduction.
As used herein, term " neurodegenerative disorders or disease " refers to those diseases that symptom is caused by the degeneration of neurocyte in the brain.Neurodegenerative diseases is any disease that causes cerebral neuron to be lost, and comprises particularly trembling and spasm that parkinson disease, Huntington Chorea, Alzheimer and apoplexy or cerebral ischemia cause.
As used herein, term " neurological disorder " refers to any obstacle of existing in brain, spinal column and linked groups such as the meninges, and described obstacle has response to suitable therapeutic agent." neurodegenerative disorders " refers to any obstacle that the carrying out property of neural cell group is dead and disappear and cause, and the occurring mode of described obstacle has been characterised in that specific morbid state, and causes cerebral lesion.
As used herein, term " tau pathological changes (taupathy) " and " tau pathological changes (taupathies) " refer to have dementia and the dyskinesia of the pathological characteristics of tau accumulation in the cell.The example of tau pathological changes includes but not limited to mongolism, Basal ganglia degeneration, frontotemporal dementia (frontotemporaldementia), Pick's disease and progressive supranuclear plasy.
Term " stress disorders " refers to by the psychiatric disorders that contacts wound or have stress event to present.Stress disorders comprises acute stress disorder, posttraumatic stress disorder and has the short-term Mental Subnormality of significance stimulus (perhaps multiple significance stimulates).Term used herein " posttraumatic stress disorder " broadly refers to the neuropathy disease, it is at DSM-IV-TR(AmericanPsychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Washington, D.C., definition 2000).DSM-IV-TR is defined as " posttraumatic stress disorder (PTSD) " and is characterised in that constantly again extremely traumatic event of experience.DSM-IV-TR has proposed to be used for the general received standard of diagnosis and classification posttraumatic stress disorder.
As used herein, term " Alzheimer (AD) " refers to that middle and late stage at life begins to demonstrate memory loss, chaotic and isotropic and usually caused dead carrying out property spirit degeneration in 5 to 10 years.From pathology; AD can be characterized by thickening, stick together and twist of nerve fiber in the cell, neurofibrillary tangles and senile plaque, and the interior nerve fiber of described cell, neurofibrillary tangles and senile plaque are had a liking for banking group (filamentous argentophilic masses with an amyloid core) by granule or fibroid with amyloid core and formed.The method that is used for diagnosis AD is known in this area.For example, can use the standard of the National Institute ofNeurological and Communicative Disorders and Stroke-Alzheimer's Disease and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) to come the diagnosis of alzheimer's disease (people such as McKhann, 1984, Neurology 34:939-944).Patient's cognitive function can be assessed (ADAS-cog by Alzheimer's DiseaseAssessment Scale-cognitive; The people such as Rosen, 1984, Am.J.Psychiatry 141:1356-1364)
Term " parkinson disease " (PD) refers to affect especially the dopaminergic neuron (dopaminergic neuron) of black substance-compact part (substantia nigra-pars compacta) and the neurodegenerative diseases of its nigrostriatum projection.As used herein, " parkinson disease (Parkinson'sdisease) ", " parkinson (Parkinson's) " and " Parkinson's disease (Parkinsonism) " be interpreted as and comprise various forms of diseases, comprises Parkinson's disease behind parkinson disease that parkinson disease after speciality parkinson disease (idiosyncratic Parkinson'sdisease), the encephalitis, drug-induced parkinson disease such as antipsychotic drug are induced and the ischemia.
As used herein, term " curcumin (two Resina Ferulae acyl methane; 1, two (the 4-hydroxy 3-methoxybenzene bases)-1 of 7-, 6-heptadiene-3, the 5-diketone) " be the chemical compound of natural generation; it is the main chromosin (coloring principle) (the 5th; 679, No. 864 United States Patent (USP)s (people such as Krackov)) of finding in the rhizome of plant Rhizoma Curcumae Longae (Curcuma longa).
Term " liposome " refers to that its wall or film are by lipid, the capsule that forms of phospholipid especially, and it randomly is attached with sterin, especially cholesterol.
As used herein, term " in the body " refers to the inside at health.Be understood to show the operation of in nonliving system, carrying out such as term " external " expectation of using in this application.
Term " gene " is used in reference to the unit of functional protein, polypeptide or encoded peptide.As those skilled in the art will appreciate that this functional term comprises genome sequence, cDNA sequence or its fragment, and perhaps its combination, and gene outcome, described gene outcome comprises can be through those of manual change.When it is separated, refer to these entities with the gene of purification, nucleic acid, protein etc. from least a general contaminated nucleic acid related with it or protein.
As used herein, " biomarker " is in fact biologic artifact arbitrarily, for example protein and its fragment, peptide, polypeptide, proteoglycan, glycoprotein, lipoprotein, carbohydrate, lipid, nucleic acid, organically or inorganic compound, natural polymer and micromolecule, described micromolecule are present in the biological sample and can separate from this biological sample or can measure in this biological sample.In addition, biomarker can be whole complete molecule or can be its part that described part can be that function is partly arranged, or partly by the identification of for example antibody or other binding proteins specifics.If biomarker can the measurement aspect and patient's given state, for example the moment of septicemia is associated, and thinks that then biomarker provides information.Like this for example can the measurement aspect can comprise this biomarker from the existence in the biological sample in the individuality, do not exist or concentration and/or its existence as the part of biomarker spectrum.
As used herein, term " receptor " comprises, for example, be positioned on the cell surface and come the molecule of the activation of mediated cell by the activation part, and it usually also is used for any molecule that expression is attached to arbitrarily counter pair (counterpart) specifically.A right member of specific binding subjectively is called " receptor " and another is called " part ".This specific binding needn't be associated with particular physiological function arbitrarily.Therefore, for example, " receptor " can comprise the molecule etc. of immunocompetence part, design and other complementary elements of antibody, antibody.In fact, under environment of the present invention, the difference between " receptor " and " part " is fully incoherent; The present invention relates to specifically in conjunction with each other molecule pair, described combination has and compares stronger affinity in conjunction with other molecules.Yet, for the ease of explaining, method of the present invention with the concept of target receptor (again, be molecule simply, for this molecule seek with its reaction or with the counter pair of its combination), and " part " represents this counter pair simply.
As used herein, term " treatment (treatment) " refers to the treatment to the disease of mentioning herein, is confirming to have among the patient of described disease or obstacle specifically.
As used herein, term " treatment (treatment) " or " treatment (treating) " refer to give arbitrarily chemical compound of the present invention, and comprise that (i) suppresses disease (namely in the animal that experiences or present ill pathology or symptom, stop further developing of pathology and/or symptom) or (ii) in the animal that experiences or present ill pathology or symptom, alleviate disease (that is, pathology and/or symptom being reversed).Term " control " has comprised the seriousness of the disease that prophylactic treatment, elimination, alleviation or minimizing are controlled.
Term " effective dose " or " treatment effective dose " meaning is that the amount of target compound can cause biology or the medicinal response that researcher, veterinary, doctor or other clinicians seek in tissue, system, animal or people as described in this article.
As used herein, term " gives (administration of) " or " administration (administering) " chemical compound is appreciated that chemical compound of the present invention to treat the upper useful amount of upper useful form and treatment, offer the individuality that needs treatment with the form that can be incorporated in the individual body, described can be incorporated in the individual body form include but not limited to: oral dosage form, for example tablet, capsule, syrup, suspension etc.; Injectable dosage form, for example IV, IM or IP etc.; The dosage form of percutaneous comprises cream (cream), gel (jellies), powder agent or patch (patches); The dosage form of direct oral cavity; The powder that sucks, spraying, suspending agent etc.; And rectal suppository.
As used herein, term " through intravenously administrable " comprise the injection and other modes through intravenously administrable.
As used herein, term " pharmaceutically acceptable " be used for to describe carrier, diluent or excipient must with other component compatibility of preparation, and be not harmful to for its recipient.
The invention describes compositions and method for relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease and stress disorders, described stress disorders comprises posttraumatic stress disorder (PTSD).The present invention has also described the pharmacology of curcumin in the people, thereby identify curcumin under the PTSD clinical setting with hippocampus as target spot in its brain, and confirmed with suitable dosage when parenteral gives curcumin, brought clinical benefit inferior the concentrating of the PTSD patient who standard care is had intractable (refractory).
Progressive Alzheimer (AD) and parkinson disease (PD) are to be main cognition and movement disorders among the crowd of over-65s at the age.Effectively on the Drug therapy part degree for the clinical symptoms of cognitive and athletic injury, but its not prevent disease make progress or be basically influential to progression of disease.The brain envirment factor comprises that the cell injury of health wound, psychological stress, chemical toxicant, metabolic induction and the known genovariation that is associated with neural inflammation, oxidative stress and protein folding distortion play important or additional effect in the neurological sexual development of AD and PD (1)These events are also induced the inflammatory process of Microglial activation, and described inflammatory process not only endangers its neuroprotective function, and cause the release of the mediation agent of inhibition chemistry and neurovirulent cytokine (2)Existence and the peroxophosphoric acid of tau of amyloid-β in the neuron (Abeta-1-42) on the histology is that the neurological of fully describing changes.Yet no matter these are the firing event of beginning or the secondary event that other zests neuro pathology reason causes it be unclear that.Other factor comprises that more indefinite cellular sensitivity in specific brain site rises, and described brain site has: the neuron of the neural stem cell of black substance compact part, striatum, dentate gyrus and CFU-GM and hippocampus.Its loss or dysfunction meeting cause motion and cognitive impairment syndrome.The prevention of these obstacles, the prevention of progression of disease or alleviation need to be for a plurality of molecule targets.These targets comprise initiation nervous process, Microglial inflammation (2), promote the nerve progress and occur and neural plasticity stimulates to replace neuron impaired or that lose by nerve (3)The factor.Up to now, require mental skill outer hepatocyte or CFU-GM are repaired with neuron replace the preclinical test level that remains on, and the benefit in the treatment is limited to doing well,improving.
Hippocampus is the funnel of the sensory information of deep processing, and it intersects at entorhinal cortex.Hippocampus is important and crucial brain complex, and it promotes to carry out function (executive function), memory reproduction, memory finishing, emotion and behavior and regulates.It is gone back and there is the several functions interconnection in the site of other controlled motion activity of brain.
The upset of hippocampus function is the direct inducement of neurological disorder, and described neurological disorder is characterised in that cognitive impairment, memory and unusual memory phenomenon.The clinical method that medicine is remedied requires to induce neural the generation and neural plasticity, recalls memory, guides, learns and replace out of order neuronal circuit thereby form (4)The hippocampus damage has changed the integration of importing sense organ or movable information and emotion experience before this or society's value into.Right hippocampus and peripheral region thereof are activated by the task of the dominant study that the non-speech of needs stimulates, and when task involves concerning between the memory stimulation, the activation of anterior hippocampus occur.When stimulation involves coding depth, and the amount that activates is when depending on coding depth, and hippocampus automatically relates to wherein.Probabilistic classification task (the people such as Knowlton, 1996) back of the body outside prefrontal lobe (dorso-lateral Pre Frontal Cortex) and RCN (right caudatenucleus) have been activated, and its performance suffers damage in parkinson disease (PD), but not infringement in the patient with medial temporal lobe pathological changes (medial temporal lobe lesions).PD patient is impaired for implicit sequence learning, and this implicit sequence learning is known to activate striatum in normal experimenter.(TOL) in the task, PD patient fails to activate RCN at Tower of London (Tower of London), but it is relevant to demonstrate task.The blood flow of brain improves in right hippocampus.Thereby this has represented raising of hippocampus and has overcome striatal defective.On the contrary, if the inhibition of hippocampus is necessary for optimal representation, hippocampus is failed inactivation and can be caused that the TOL task obtains impaired performance among the PD patient.
The damage of hippocampus is adjusted in the obstacle (PTSD) after also involving wound, adjust obstacle after the described wound and be a kind ofly come back from fight life-threatening event, natural disaster, accident and wound, veteran, after terrorist incident and the violence individual aggression, psychiatric disturbance chronic and that make people's weakness.The complicated part of PTSD therapy is related obstacle for example drug dependence, depression, memory and cognition problem.Lifetime prevalence is 10-30% in the disaster sample in the scope of 3-8% in community's sample, is 15-27% in war/fight veteran sample, and is 20-40% in the assault sexually sample.The etiology of considering PTSD needs to involve the cerebral neuron loop that corresponding danger is responded maps, frightened regulate and the study of disappearing (extinction learning) (challenge of conditionality scared response) is that important still to compare the very important simpler practical pharmacotherapy of the present invention more complicated out and away.
The PTSD among the American that grows up according to estimates, the lifelong sickness rate of the obstacle of lasting for years is 6.8% (20)Male's PTSD sickness rate is 30.9% and the women is 26.9% in the veteran that U.S. the Vietnam War is striven.There are approximately 1700000 veterans to experience " clinically serious stress symptom " (21).At present, in Iraq and Afghan conflict the masculinity and femininity of being on active service has there been brought great impact in the problem of Mental Health.In the war in Iraq and Afghanistan, 20% in 230000 soldiers, i.e. 49425 recently diagnosis of veteran have PTSD.Need to pay wages based on the PTSD in 2 years of sign treatment from Iraq and the Afghan army that comes back at 1,500,000 be 4.3 to 6.2 hundred million dollars.The spending in 2 years of each case is 5900 to 10300 dollars.Treatment of the same period need to be carried out on every Mondays course for the treatment of in 10-12 week, and is less than 10% people and has finished treatment.Even when with the time lengthening to 52 of operable treatment week, only be less than 30% the treatment of having finished.Receive the Mental Health treatment course for the treatment of of recommended amount the veteran who only has minority of veterans administration's practice section facility acceptance nursing.Except individual's difficulty, nursing also has substantial difficulty on system level.Be lower than 25 years old, in the diagnosis of basic nursing clinic with in the veteran of grass roots life, the male compares the more impossible sufficient nursing of accepting with the women.In addition, current treatment standard has its shortcoming, and this also is to hinder.Demand with veteran of PTSD is not satisfied, and comprises suicide, Drug abuse, followed the coexistence diseases such as depression of Various Complex medical problem all to emphasize just to provide in the VA system service that increasing demand is arranged.
Over past ten years, extensively recognized by excessive health and psychic trauma or the excessive clinical obstacle that stress cause.Word " stress " refer to be applied to individual wound environment, health and physiology power.This word stress use under the environment of medical science obstacle be hold intelligible.Yet, induce stress multiple health and emotional trauma experience and individual personality together so that stress and obstacle between relation smudgy.When the patient of diagnosis and treatment stress-related disorder in order to improve homogeneity, when the age scope, face dead intensity, death threats and the health violence that runs into be relative near the time, be necessary to select for example smell of powder of similar deciding factor.
Among 20% veteran who survives in trauma stress, life may demonstrate the S﹠S of mental disorder, and described mental disorder is by making us weak stress-induced.This posttraumatic stress disorder (PTSD) is characterised in that with remembering processes relevant health and the uneasiness of emotion.The tendency that PTSD occurs is difficult to judge because different soldiers restrain oneself stress ability different.Therefore, according to individual's background, being exposed to similar Traumatic Events can alleviate, and perhaps increases the weight of and develops into PTSD.Clinically, the zone that the understanding that wound obstacle memory is processed and resolution concentrate on brain control memory, for example variation of hippocampus, described memory are processed and are namely recorded, store and discharge recent and old memory.The minimizing of dissection disturbance or hippocampus volume is technical can carry out imaging, and is associated with PTSD.In external and animal model at stress-related disorder, the variation of the blood volume in the brain and hippocampus component of organization has disclosed some stress convert the deduction mechanism of PTSD to.These have supported feasible hypothesis, make it possible to new medical supervision is selected to screen and evaluate.These observed results show that strongly hippocampus is the target that empirical tests is associated with PTSD.The effort of neuropathy medicine, cognitive psychological therapy and social support through license that is used for the treatment of PTSD that applies demonstrated be moderate but incomplete benefit, this be because and the lasting physiology that combines of the neuranagenesis ability that weakens-pathology change and help keeping of PTSD state.Fight veteran quantity with PTSD increases, and the inadequate confirmation of medical treatment and nursing structure should be invested in extra treatment research.
Treatment has comprised the cognitive psychological therapy, yet doctor's preference is treated Symptomatic PTSD patient by medicine, yet the medicine that needs effectively, has the good safety spectrum, can obtain, practicality be arranged and afford is arranged, thereby the patient under varying environment can benefit therefrom.The treatment of current license comprises five hydroxytryptamine reuptake inhibitor Sertraline and paroxetine, be used for treating PTSD the adult, yet the improvement of these treatments is not universality, and its in clinical practice and the application quality in community-based health care differ.
Reported curcumin by addressing these problems in stimulated in vitro hippocampus CFU-GM and hepatocyte, and impaired Hippocampus nerve is taken a turn for the worse.In the research, curcumin has hindered 5-HT(1A in vivo) neurotrophic factor (BDNF) protein level that produces of mRNA, brain and by excite nerve reduction under the stress-induced that occurs of serotonin-1-A receptor and BNDF (5)Suppose to have neural plasticity and the animal migration of inducing, these new neurons can be replaced the impaired or destroyed neuron in other positions in the brain.In order to prevent, prevent or repair carrying out property deterioration of neurons, medicine must can pass blood brain barrier, and brain essence has adverse events seldom or that do not follow, must be controlled in the essence by suitable drug transporter, and reach treatment concentration in the gathering of affected position.
The curcumin band that uses is in the present invention served unique feature, and this makes it become attractive candidate in PTSD and the PD treatment.(i) curcumin hinders neuronic death in the animal model of neurodegenerative diseases, (ii) in the dentate gyrus of developmental and adult mice hippocampus, curcumin to Mus versatility neural progenitor cell (NPC) show two phase effects (under the low concentration=mutation; Under the high concentration=suppress); (iii) curcumin active cell external signal associated kinase (Arks) and p38 kinases: improve neuron plasticity, improve and neurally to occur and induce the oxidation of haemachrome with Nrf2-ARE in the tumor cell, described haemachrome is cytoprotective albumen in neuron, (iv) in tumor cell, the growth factor signal transduction pathway of curcumin inhibition and ERK and protein kinase C coupling, (v) curcumin reduces and old and feeble oxidative damage and the cognitive impairment that is associated, (vi) curcumin is for exitotoxicity and traumatic damage protection hippocampus neuron, (vii) curcumin is controlled radical scavenging properties under high μ Μ ο l concentration, under low concentration, can activate/the Inhibitory signal transduction pathway, (viii) under 0.1-0.5 μ Μ (500nM) x 24-48h, improve the propagation of NPC and do not improve the propagation of tumor cell; 〉 reduce the propagation of NPC and cancerous cell under the 10uM, and (ix) general lumbar injection (i.p.) curcumin@500nM/kg x 4 days, in blood peak concentration be 5-6 μ Μ and in brain peak concentration be 1-2 μ Μ.
The invention discloses the significant improvement in the PTSD clinic control.Inventor's plan is diagnosed liposomal curcumin through vein has the after the war discharged soldier of PTSD, and estimates its safety and effectiveness.This medicine passes through blood brain barrier, is directed in hippocampus and the striatum, hinders the neuronal cell injury of stress-induced, and the reparation in excite nerve generation and injured neurons loop.
To an open question still, the PTSD therapeutic modality changes can turn out to be more efficiently treatment, uses chemotherapeutant in the described variation, and this chemotherapeutant is targeted to the damage of stress-induced in the previously described Key neural units site specifically.
The war discharged soldier quantity of suffering from PTSD increases this problem, the random time process that clinical sign and symptom occur, the chronicity that in long-time, needs acute and long-term intervention, the jejune state of objective diagnosis method, nursing and send the deficiency of standard, and the mistake of psychological mode and current Therapeutic Method is expensive has proved new therapeutic scheme of the present invention.The demand of the new therapeutic scheme that proof is described in this article is the growth with postwar discharged soldier crowd of obvious emotion and coexisting issues, the productivity's of the unstable and reduction of the destruction of the cost of medical control, society, civilian labor force result.Although it is also immature to consider to get up, increase the off chance that effective therapy can allow preventative assembly, described preventative assembly is used for reducing the relevant obstacle of trauma stress and improves afield armed personnel's overall technical ability.
The invention solves unconsummated medical need, the common people that reduced the spending of medical science and social influence and reduced obstacle that stress be relevant experience the precursor of deduction.In affected crowd, have that concurrent situation is for example indulged in excessive drinking, smoking, drug dependence and a suicide, if these situations are alleviated, will bring significant benefit.Since need to be to the treatment of hippocampus defective associated disorders in the aging and other neurological dementias, therefore the hippocampus damage shows some actual benefits after diagnosis and the treatment trauma stress.
The checking of problem can be judged from existing report, the existing number (20) that is reported as the patient who is subject to the PTSD impact, psychology and medical intervention estimate with the cost that improves, and society since the individuality with chronic PTSD without fully treating the loss that is subject to.Improvement meeting in the PTSD individuality on the objective and symptom brings active influence for crowd's finance and the productivity.
Example I
The purposes of curcumin in nervus retrogression and neurological disorder
The Hippocampus nerve occurs in environmental condition and the lower impact that improves and be subject to AD, aging and diabetes of dietary energy restriction, and described environmental condition improves learning and memory, for example examination.Curcumin improves the neural generation of Hippocampus when 500nM.Curcumin is by inducing low sugar consumption, reducing serum cortex fat ketone, the catalytic activity that improves adenosine cyclase (AC) and the level of cAMP in different brain regions, the mrna expression that raises AC hypotype AC2, AC8 and cAMP response element binding protein (CREB) in the hippocampus of hippocampus, cortex and CUMS rat improves chronic stress (CUMS).Its ultimate principle is as antidepressant (17)Curcumin uses the memory ability that improves the Alzheimer mice incubation period (oral administration gives ALCL3 and gave the D-galactose 90 days through IP) of keeping away dark test (step-through test) and prolonging, and the apoptosis that inhibition is induced by A1C13 in PC 12 cells of cultivating.Mechanism table understands that BCL2 improves, and BAX (18)Do not improve.Curcumin has antioxidation in aging rats, the lipotropism class merges (antilipofusinogenesic) and defying age effect (19)
The inventor is used for neurological based on vitro data with the curcumin exploitation and uses, and in described vitro data, curcumin excites neural generation, synaptogensis and migration in deriving from the adult neural stem cell of brain (3)Additional animal and biochemical analysis show that also as antioxidant, it has epigenetic effect: it has reduced histone H 3 and H4 acetylation to curcumin, and namely it works as histone acetyl transferase inhibitors and acetyl group deacetylase inhibitor (7,8)These activity are tended to Inhibited differentiation in astrocyte, and promote neuronic differentiation.
Since the insolubility of curcumin in aqueous medium, and the bioavailability when the oral route administration is very low, and the inventor has developed liposomal curcumin, polymer nanocomposite curcumin
Figure BDA00002418246400171
And PLGA (PLGA) curcumin, soluble preparation comes for through intravenously administrable in blood (9,10,11)Curcumin in these preparations synthesizes 99.2% purity under the GMP condition.The inventor has determined these three preparations in the passage of crossing blood brain barrier after intravenous bolus injection technique in rat and brain inner tissue pharmacokinetics, thereby the curcumin that is determined in the brain essence distributes and its may distribute in the specific brain regions zone related with neurological disorder.
Curcumin is by Sami Labs, Sabinsa Corporation, Bangalore, India are synthesized to 99.2% purity, and liposome, PLGA curcumin and
Figure BDA00002418246400172
Use in the preparation.PLGA is available from Surmodic Pharmaceuticals, Inc.Birmingham, and Alabama, and the PLGA-curcumin preparation is at University of North Texas Health Sciences Center, Ft.Worth, and Texas is synthetic. Use available from the acrylate copolymer of Surmodics Inc. synthetic at Johns Hopkins Hospital Cancer Center.Liposomal curcumin is at Polymun Scientific GmbH, and ViennaAustria is synthetic.
Having bought weight from Charles River PQ Canada is the SD rat of 250g, and makes it in 12 hours light of 7 days endoadaptations-dark cycle.Commercial feedstuff, tap water is provided and strictly keeps according to institute animal care guide to it.This research approach is by University of WesternOntario, and Canada Animal Health Care Committee checks and approves.The approach of selecting tail vein to give as medicine because its require minimum restriction and induce seldom stress.With liposomal curcumin with 20mg/kg without carrying out dilutedly an injection.Will
Figure BDA00002418246400181
In 0.9% normal saline, dissolve, and carry out a notes administration with 5mg/kg, and the PLGA curcumin that will be dissolved in the distilled water carries out a notes administration with 20mg/kg.Collect blood sample according to interval by cardiac puncture after the injection, subsequently mice is put to death by KET anesthesia.For each dosage with at the interval of, two and four hours after intravenous injection, use 3 to 4 rats.After KET is put to death, its brain is removed at once, and cortex, left hippocampus and right hippocampus, brain stem (medullary substance, pons and midbrain) and striatum are cut at sled, weigh and prepare to carry out the HPLC analysis.Other brain zone, blood plasma, spleen, kidney and liver are weighed, and promptly freezing in liquid nitrogen and storage is used for further analyzing.
The specimen of weighing is homogenized in 20% PBS.Each cerebral tissue that homogenizes of 200 microlitres is transferred in the micro-centrifuge tube of amber labelling, to the interior mark of 0.15 μ l/ml (IS) acetonitrile solution that wherein adds 200 μ l.For the curcumin standard substance, the cerebral tissue that homogenize, that process without curcumin of 180 μ L is transferred in the micro-centrifuge tube of four amber labellings.The 0.15 μ l/ml IS solution that adds respectively 200 μ l in the known curcumin standard substance (0.5 μ g/mL, 1.25 μ g/mL, 2.5 μ g/mL and 5.0 μ g/mL) with backward 20 μ L.For the negative control of blank, add the contrast cerebral tissue that homogenizes of 200 μ L and the IS solution of 200 μ L.The all vortex concussions 10 minutes of the whole sample with IS, contrast and standard substance, and under 6000RPM centrifugal 5 minutes subsequently.The supernatant of each sample is removed, and after the nylon injection filter of this supernatant by 0.22 μ M filtered, each sample of 50 μ L is expelled in the HPLC system.In order to carry out determination of plasma, the various blood plasma of 200 μ L of each rat are transferred in the micro-centrifuge tube of amber labelling, add therein the IS of 200 μ L.For the curcumin standard substance, join the blood plasma of processing without curcumin of 180 μ L in 4 micro-centrifuge tubes and add respectively the curcumin of 20 μ L (0.5,1.25,2.5 and 5.0 μ g/mL respectively), add the IS solution of 200 μ L.For negative blank, used contrast blood plasma and the IS solution of 200 μ L.All samples with interior mark (IS), contrast and standard substance are vortex concussion 10 minutes and under 6000RPM centrifugal 5 minutes all.The supernatant of each sample nylon injection filter by 0.22 μ M is filtered, and the final volume of 50 μ L is expelled in the HPLC system.
The curcumin standard substance and as interior target emodin available from National Institute for the controlof Pharmaceutical and Biological Products (Bejing, China).With these curcumin standard substance and by Sabinsa Inc., Bangalore, synthetic other curcumin of GMP level of India compares.For the mensuration of curcumin in blood plasma and tissue, the method that the inventor has used Li to adopt (13)
Method of the present invention is closely according to the guide of U.S.'s good laboratory standard (GLP).HPLC analyzes and carries out on the Water HPLC System (Waters, MA, USA) that is comprised of Waters 1525 binary pump, 2487 double suction photometric detectors and Waters Breeze Software3.3 version.The measurement of curcumin is used has Inspire C18 post (4.6x 100mm, the particle size of 5 μ m) Kikma Technologies, Bejing, China.) Water HPLC System carry out.Mobile phase is made of acetonitrile and 5% acetic acid, and (75:25, v/v), flow velocity are 1.0mL/ minute.Mobile phase is filtered through the nylon membrane filter of 0.45 μ Μ, and ultrasonic degas before use.Detecting wavelength is 420nm.Volume injected is 50 μ L, and be each sample 5 minutes under the room temperature analysis time.
Shown in standard curve (Fig. 1), according to the mensuration of HPLC, the relative area of plasma adiponectin plastid curcumin standard substance is linear in the scope of 1 μ g-12 μ g/5.0 μ L sample.In the situation of not any chemistry before this or that follow or physical operations, for Liposomal formulation, organize curcumin in hippocampus and in the brain that merges: the individuality under 4 hours intervals frequently of blood curcumin is larger.As showing shown in the 1-3, for the PLGA curcumin, 2 hours lower striatums: the ratio of blood has shown that the measured value of tissue does not reflect the curcumin of blood vessel, and the chemical compound of these preparations passes through blood brain barrier similarly.The location of these three kinds of preparations and the variation of clearance rate show that single preparation can be regulated brain PK character.
Curcumin mainly can in hippocampus, brain stem and striatum, detect total injected dose less than 0.5% level.Liposomal curcumin concentration in hippocampus and striatum zone reached peak value in 2 hours.The brain zone of the merging except striatum and hippocampus have seldom or do not have a detectable curcumin, this has shown optionally deposition.In these two positions, the clearance rate relevant from inject time also is different.In the time of 2 hours, the content of curcumin is than high 2 times in the hippocampus in the striatum, and after peak concentration, the removing in the striatum is than larger (table 1) in the hippocampus.
Table 1: give liposomal curcumin (20mg/kg) through vein after, average cerebral tissue and blood plasma curcumin level in the rat.
Numeric representation is meansigma methods ± SEM.(n=4 in each interval)
Because supply is limited,
Figure BDA00002418246400202
Distribution research in the total curcumin dosage of injection reduce to 5mg/kg.Significant accumulation is arranged, and the hippocampus locating speed is a little faster than viewed in the liposome prepared product in brain stem, and CLTB is than striatum slower (table 2).In this research, the removing from blood plasma between 1 to 2 hour is less than the liposomal curcumin viewed.The decline of curcumin level and the decline in the blood plasma are not proportional in cerebral tissue.Suppose the logic that has of observing when the curcumin level of observing is higher than 2 hours in 1 hour.Compare with liposomal curcumin,
Figure BDA00002418246400203
Notice afterwards in hippocampus than higher curcumin level is arranged in the striatum.
For the PLGA-curcumin of 20mg/kg, the IV dosage of curcumin is the curcumin (table 3) of 2mg/kg when proofreading and correct PLGA to the ratio of curcumin.Picked-up in striatum is the highest, follows by hippocampus and brain stem.After IV injection, observed high cerebral tissue/blood plasma ratio in 2 hours.After injecting 4 hours, the curcumin level of blood plasma has descended 50%, and the curcumin level of striatum and brain stem can not detect.Keep relatively constant in after injection 4 hours of the curcumin level of hippocampus.
Table 2: giving through vein
Figure BDA00002418246400204
(5.0mg/kg) the curcumin level of average cerebral tissue and blood plasma in the rear rat.
Figure BDA00002418246400205
For the group (n=1) of 1 hour group (n=2) and 2 hours, numeric representation is meansigma methods ± SEM.Because when carry out this research
Figure BDA00002418246400211
Supply limited, be 1.6% or 0.08mg/kg as the total curcumin of main active component injection.
Behind vein group injection curcumin preparation, confirmed to pass the blood brain barrier of rat.Based in mice, giving through intraperitoneal before this
Figure BDA00002418246400212
Research (6), it is not beat all passing blood brain barrier and the anti-inflammatory in its brain and non-oxidizability.The curcumin of preparation passes blood brain barrier can be suppressed active by the diffusion of cross-film, permeable transportation, absorbefacient endocytosis and extracellular approach and MDR-1 and occur or by its promotion.The solubilising component is unknown for drug diffusion, transportation and the impact of removing from brain essence, because the effect of liposome, polymer and PLGA chemical constitution is exactly so, however these three preparations its can change and the removing difference observed be brought contribution the location.
Table 3: giving PLGA-curcumin (20mg/kg) through vein afterwards, the average cerebral tissue in rat and blood plasma curcumin level.
Figure BDA00002418246400213
Numeric representation is meansigma methods ± SEM.The n=3/ group.For curcumin-PLGA, the purity of free curcumin be 99.2% and comparing of free curcumin and PLGA copolymer be 1:9, what therefore dissociate curcumin in curcumin-PLGA preparation is 2mg/kg through vein dosage.
Although this dosage is different in these researchs, importantly curcumin preparation is by blood brain barrier, and described blood brain barrier is the obstacle in the treatment for the treatment of neurological disorder.But owing to the availability of medicine, used rat and the sampling number of limited quantity for each preparation of testing.
But in these three kinds of preparations the checkout discrepancy of diverse location reflected blood flow, compile, retain and flow out the clean impact of character.The angiological anatomy of diverse location can be considered to the contributive factor in rat, but injected liposome and
Figure BDA00002418246400214
Rat in the high level of striatum and the brain stem mankind that may not derive respectively, this be since the research that in the patient, regional flow and high-resolution histology is associated openly hippocampus, striatum is compared with the remainder of brain with the vascularity in the brain stem that any relative growth is not arranged (14)Different accumulating rate and remove parameter and can reflect site-specific variable histologic characteristics, Interstitial cell outer void for example is from transhipment distance and a matter pressure of vascular system.Have between outside radiation transit area high matter pressure by oppositely can hindering overflowing of medicine and fluid to internal diffusion, and can reduce and cross the speed that transport at fluid interval, extracellular.
The focusing of these three kinds of curcumin preparations in the specific brain regions zone distributes and picked-up, and to this optionally the site locate contributive mechanism and remain ambiguous, and can not explain that by passive process described passive process depends on physicochemical properties for example lipotropy or molecular weight.Yet drug transporter may have influence on pharmacokinetics and the location, site of curcumin in the brain.These transhipment have been eliminated organic anion (OAT) or cation (OCT) from brain, and express in hippocampus, cerebellum and cerebral cortex widely.Their role is to prevent the accumulation of exogenous material, neurotoxin and neurotransmitter.Because the PLGA molecule is electronegative, use the conduit of OAT can be to being positioned with contribution, but this can not explain lacking of distributing in cerebellum and cortex.
These all features all have influence on the time that arrives periphery, interested cell site from being discharged into medicine, and it is independent of diffusion rate, and described diffusion rate depends on bulk of molecule.The size of molecule is larger, and the diffusion rate of mobility and inherence is just less.
Can be partly by the parenchyma transhipment parameter between the several districts of record although IC curcumin distributes, and be described without the two-zone model of the brain/plasma concentration of combination, still ambiguous is for the contributive mechanism of distribution, location and retention time and assembly in hippocampus, striatum and brain stem zone.According to the specific cerebral localization pattern of different chemical compounds, curcumin be not unique aspect its pharmacological action.Circumstantial evidence in the research of Oral Administration in Rats arsenite represents, when the dosage that gives 20mg/kg in the time of 28 days arsenite induced the nerve of neuroethology to shift toxicity, described toxicity shows the seriousness of oxidative stress, the product Dopamine of change, the nitric oxide in the amine of source of students, metabolite and corpse striatum, hippocampus and the frontal lobe.These illeffectss by the curcumin of a large amount of oral doses the time treatment offset, described curcumin dosage is 100mg/kg x every day 28 days (15).
The distribution of specific of curcumin for the treatment of concentration is the evidence of potential effect of the curcumin treatment of neuropathy obstacle.On clinical response, can occur based on different cerebral localization speed the difference of curcumin preparation and the speed of administration (dosage).Group's dosage (carrying out the drug delivery of higher concentration within the short time period) can improve damage under the cost of bad normal surrounding tissue toxicity position is not especially when the position in damage has compensatory removing.For example, medicine enter and the removing from brain and peripheral nervous loop is subject to the impact of blood brain barrier, yet but the little lipid soluble drug of intracapsular injection may be invalid because most of blood that from brain, flows out to.For the transvenous constant speed gasing injection of the medicine of doses, depend on the susceptiveness of target cell, can be accompanied by the therapeutic effect of raising, described dosage produces the normal structure toxic effect that reduces according to calculating.This especially is suitable for for hippocampus stem cell and neural progenitor cell, and wherein the curcumin of low concentration (500nM) stimulates, and the curcumin of high concentration (10 μ Μ) suppresses neural generation and neural plasticity (3)
The target call for the treatment of nerve injury is prevented the degeneration process and is remedied.About these three kinds of preparations, demonstrate preparation that active root slowly discharges can show with the lipid environment in clinical advantages that more stabilizing polymer is relevant: pass permeability, the cellular uptake of gap tissue, and the raising that in selected site, keeps.What this was made contributions is its basic physicochemical properties, i.e. size, electric charge and hydrophobicity.Curative effect among the patient can also depend on the stage of disease, the location type of damage, location and the reservation of active substance.In general, its space attribute is probably depended in the requirement that has damage of high correction for treatment.The europathology damage that is associated with neurological disorder has nondispersive space attribute (relative separation site, for example parkinson disease or PTSD) or according to the maturity of disease disperse-attribute (Alzheimer) of non--dispersion, the latter can affect the remission effect of curcumin.
The normal brain cell of growing up is set, and can improve according to the concentration generating function of medicine or suppress after being exposed to curcumin.The additive factors that affects the curcumin curative effect comprised infusion of drug speed, infusion persistent period, tissue infiltration, locus specificity, from blood, be scavenged in the damage, the transmission constant of damage and normal structure is (if improve, the probability of the pathological changes through correcting also can increase, because the diffusion of independent brain is coarse, and be main by the diffusion that infusion causes), and the progress of damage growth rate or disease.These same parameters are applicable to the neural precursor in the hippocampus dentate gyrus.These are subject to inducing the impact (curcumin of low concentration, epidermal growth factor, physical activity) of neurogenetic reagent easily.Under this environment, interested nerve injury that can targeting can have high cell density and highly concentrated spatial mode, and this makes it more be applicable to treatment.Medicine removing factor is important similarly, because if its minimizing, and when drug osmotic improves, and in the situation that the medicine non-dispersive distributes, the probability of correcting subsequently can improve.
In the research of using rat, after intravenous injection liposomal curcumin, polymer nanocomposite curcumin and PLGA-curcumin, it has shown that by blood brain barrier and the site that is distributed to the nervous system disease association of supposition the obstacle of curcumin in the treatment of disease of brain is used can overcome.Use has chemically or causes the hippocampus of disease or striatum assessment animal model with radiating, should be able to measure which is that treatment is upper optimum in these three kinds of preparations.
Because curcumin can be used as mitogen the hippocampus stem cell is worked, and induce these cellular integration to functional nervous system, it should be induced and repair loss or impaired hippocampus neural stem cell in AD and PD (3)As the support to this probability, confirmed to have neuroprotective activity through endoperitoneal curcumin for the homocysteine that is injected directly in the hippocampus (16)
Data represented in the preamble show, after intravenous injection, by liposome, acrylate copolymer
Figure BDA00002418246400241
Cross blood brain barrier with the curcumin preparation that PLGA forms, and preferably in hippocampus, striatum and brain stem, locate.Think have antioxidation, anti-inflammatory, neural occur and the concentration of neural plasticity activity under, the observed result that curcumin is located in specific brain site has been supported several the comprise prevention of Alzheimer and Parkinsonian neurological disorder, the clinical practices for the treatment of and remedying.Because in these specific sites, preparation and dose dependent accumulation rate and residence time can determine its clinical efficacy, need data to plan and carry out evidential clinical experiment treatment example, described data are about the arrangement of various preparations in the animal model of neurological disorder and dosage response property.
Example II
The application of curcumin in posttraumatic stress disorder (PTSD)
The inventor is based on curcumin purposes as medicine in traditional treatment, and based on its chemical property of exploration with at the external publication that reaches the pharmacological property in rodent, the selection curcumin is as lead compound.The inventor uses three kinds of transvenous preparations, liposome, polymer and targeting antibodies-PLGA-curcumin.These preparations have been avoided the bioavailability of the limited dissolubility of curcumin and inappreciable oral administration.
The inventor has confirmed that from evidence blood brain barrier is crossed in being distributed in of transvenous liposome and polymer nanocomposite curcumin in the mice, and is positioned in the rat brain: mainly be arranged in striatum and hippocampus.Arrive rat after 2 hours through intravenous injection 20mg/kg liposomal curcumin, average curcumin level (ng/g) in striatum is 165.3ng/ml, it is 83.4 and is 42.8 in the brain that merges at hippocampus, and be 165.7ng/ml in blood plasma, this can explain by the again distribution from the brain to blood plasma.The preference of the liposomal curcumin of observing in hippocampus and striatum is the core of the Therapeutic Method described in this article, because itself and before this research are consistent, described research before this reported external and in vivo curcumin in the neural generation of hippocampus moderate stimulation (23)The inventor has confirmed that in the model of animal allograft, liposomal curcumin is activated to the cancer of pancreas, breast and colon.Compare with the data of emphasizing the oral administration safety of publishing, the inventor observes in dog that haemolysis is main untoward reaction when dosage is higher than treatment level.
Hippocampus is the funnel of the sensory information of deep processing, and it intersects at entorhinal cortex.The hippocampus damage has changed the integration of importing sense organ or movable information and emotion experience before this or society's value into.Right hippocampus and peripheral region thereof are activated by the task of the dominant study that the non-speech of needs stimulates, and when task involves concerning between the memory stimulation, the activation of anterior hippocampus occur.When stimulation involves coding depth, and the amount that activates is when depending on coding depth, and hippocampus automatically relates to wherein.Probabilistic classification task people such as (, 1996) Knowlton has activated back of the body outside prefrontal lobe and RCN, and its performance suffers damage in parkinson disease (PD), but not infringement in the patient with medial temporal lobe pathological changes.PD patient is impaired for implicit sequence learning, and this implicit sequence learning is known to activate striatum in normal experimenter.In Tower of London (TOL) task, PD patient fails to activate RCN, but it is relevant to demonstrate task.The blood flow of brain improves in right hippocampus.Thereby this has represented raising of hippocampus and has overcome striatal defective.On the contrary, if the inhibition of hippocampus is necessary for optimal representation, hippocampus is failed inactivation and can be caused that the TOL task obtains impaired performance among the PD patient.
Neural progenitor cell (NPC) is the source of all neurons and neurogliocyte in the embryo development procedure midbrain.In adult's brain, hippocampus and corticocerebral chamber lower area have kept can move, divides and be divided into neuronic NPC.NPC is to physical exercise, goes on a diet and the mitogenesis that wound is made and the response (survival response) of surviving.The propagation of chronic stress infringement NPC, this can be reversed by curcumin.Adult's nerve occurs in figure in the learning and memory process.
The curcumin band that uses is in the present invention served unique feature, and this makes it become attractive candidate in PTSD and the PD treatment.(i) curcumin hinders neuronic death in the animal model of neurodegenerative diseases, (ii) in the dentate gyrus of developmental and adult mice hippocampus, curcumin to Mus versatility neural progenitor cell (NPC) show two phase effects (under the low concentration=mutation; Under the high concentration=suppress); (iii) curcumin active cell external signal associated kinase (Arks) and p38 kinases: improve neuron plasticity, improve and neurally to occur and induce heme oxidase with Nrf2-ARE in the tumor cell, described heme oxidase is cytoprotective albumen in neuron, (iv) in tumor cell, the growth factor signal transduction pathway of curcumin inhibition and ERK and protein kinase C coupling, (v) curcumin reduces and old and feeble oxidative damage and the cognitive impairment that is associated, (vi) curcumin is for exitotoxicity and traumatic damage protection hippocampus neuron, (vii) curcumin is controlled radical scavenging properties under high μ Μ ο l concentration, under low concentration, can activate/the Inhibitory signal transduction pathway, (viii) under 0.1-0.5 μ Μ (500nM) x 24-48h, improve the propagation of NPC and do not improve the propagation of tumor cell; 〉 reduce the propagation of NPC and cancerous cell under the 10uM, and (ix) general lumbar injection (i.p.) curcumin@500nM/kg x 4 days, in blood peak concentration be 5-6 μ Μ and in brain peak concentration be 1-2 μ Μ.
The Hippocampus nerve occurs in environmental condition and the lower impact that improves and be subject to AD, aging and diabetes of dietary energy restriction, and described environmental condition improves learning and memory, for example examination.Curcumin improves the neural generation of Hippocampus when 500nM.
The PTSD problem infer solution: use the external and animal model of stress-related disorder, the change of cerebrum blood and hippocampus structural constituent has disclosed some physiopathologys of hippocampus damage.People's imaging research has also confirmed functional change in crucial brain zone.Summary to the plastic change of PTSD midbrain has shown the position that involves in the core symptom of PTSD: excessively awakening (hyper-arousal), intrusion imaging (intrusive imageries), nightmare (nightmare) and emotion numbness are inboard prefrontal cortex (medial prefrontal cortex), hippocampus and corpus amygdaloideum (amygdala).The sign support is arranged, stress in PTSD, play negative impact to the Hippocampus nerve.Antidepressant, environment change and physical exercise have some beneficial effects to the nerve that reverses stress-induced.Yet, lack and be targeted to neurogenetic specific medication candidate.
The pathophysiology that rear life system participates in PTSD has been proposed.But, with limited rear living observed result and the drug candidate person that the infers challenge that interrelated.Unlike the determiner of gene structure, rear living signal concentrates on specific gene outcome " opens or close ".Some components of rear life system, namely the balance between dna methylation and the histone acetylation and deacetylation can change the course of disease of PTSD.
Memory coding is carried out in phosphorylation and acetylation that transcription activating after stress event causes being accompanied by histone H 3 in the dentate gyrus.Confirmed in the research before this that curcumin chemical compounds HDAC suppresses active and works as the histone deacetylase enzyme, and can affect the memory mechanism in hippocampus.
The curcumin preparation of the nano-scale liposomal curcumin of describing in this article provides rare chance to explain experimental embryology among the PTSD and the complexity of gene-environment interaction, and further explores the curcumin therapy under the environment that its new HDAC suppresses.Liposomal curcumin is located in hippocampus, and implements the hippocampus institute role that clinical trial need to be understood the crucial center of wound and conduct memory processing with transvenous preparation as the possible alleviant of PTSD as described in this article.Hippocampus depends on a plurality of sense organ inputs in function.In case information arrives hippocampus, hippocampus will be to its processing and storage.This information can be inertia, perhaps can transfer to actively a plurality of motions and sensory effect's device, and the clinical emotion that is shown as.The mechanism that merges, keeps, recalls and cause the emotionality reaction has been set up the environment of controlling any specific stress event.Therefore, the health of hippocampus is measuring stress tolerance.Excessively health wound or psychological life-threatening event, perhaps the stressor of both combining forms can cause the somatic pathology damage of Hippocampus, and to recurrence stress tolerance reduce.The end product of the damage of inducing can have contribution to PTSD and the depression of following (23)
Important query is, why this specific site should be subject to the impact of indirect trauma easily.Relative reflection simple or evolution conservative with condition is compared, and " moving component (movingparts) " of Various Complex arranged, and characterizes it so that plasticity and the adaptability of the impact that sustains damage easily.This sensitivity shows as by neural stem cell/precursor and compensates, and described neural stem cell/precursor has represented the fail-safe mechanism that the neurocyte that stress the cause loss of normal fatigue and destruction, aging and excessive wound-induced is responsible for.At present to also very limited with the interactional research of the pharmacology of these cells (23)
The probability that meets with serious poor environment is not uncommon in the situation of fight, and traumatic physiological and pathological has influence on hippocampus in the described poor environment.When this happens, individuality may demonstrate the S﹠S that has the instant of PTSD feature or postpone.This is diagnosed in 1980 and is written as first code, and has delivered DSM-III.Therefore, identification has the individual need trauma history of PTSD, and which its which part of also measuring this obstacle in order successfully to carry out clinically extra research can treat and measure and partly can to simultaneously treatment opposing be arranged owing to the loss of the neurocyte on the pathology.Because manpower demand and multifaceted method long-term and consuming time, the great financial burden of fully PTSD veteran has been reintroduced to the composition of society that works orderly individual and society.Treatment in traditional and the test is the interim psychiatry spectrum that changes in the military exercises that comprised at the same time, embolic chemotherapy, described embolic chemotherapy have comprised that the medicine that uses multiple exploitation to be used for the treatment of other mental disorders such as antidepressant, tranquillizer, mood regulation agent etc. treat.
With concentrate the damage position that stress be associated for example hippocampus be that feature by several uniquenesses consists of as the probability of primary treatment target.Except it is the center of memory processing, its for direct health and indirectly psychic trauma, to follow aging and vasculitic denervation be sensitive.The hippocampus dysfunction is associated with other neuropathy, and described neuropathy is Alzheimer, temporal lobe dementia and parkinson disease for example.From positive aspect, the existence of neural stem cell makes it possible to carry out that mitosis spontaneous or that induce stimulates and the reparation of neural complex or reconnect.The latter's probability is being interesting based on enlivening in the neural recurrent reparation research, and this is owing to be excluded in the inspection of spontaneous reversible activity outside animal model by wound inducement.The availability of the PET scanning of the technology of Noninvasive such as measurement function or size becomes more valuable, and this is because the improvement in the detection of impaired hippocampus is become possibility.
The hypothesis of onset of the present invention be PTSD with acute and severe stress after the neuro pathology of hippocampus relevant, this hypothesis does not limit the present invention.Current not for the chemotherapy of repairing the problem of this obstacle in the hippocampus level.This requires drug distribution in the site that involves and the neurocyte reparation, is contemplated that in the described neurocyte reparation that loss and impaired neurocyte are from the reverse that can cause hippocampus functional disorder aspect of inducing of body replacement.The latter's probability can be studied with representational animal model.Liposomal curcumin satisfied medicine cross blood brain barrier, under the suitable concentration to normal cerebral tissue do not have toxicity, in the requirement that after the parenteral infusion, navigates in the hippocampus and work as the neural stem cell mitogen.Under this background, and consider that hippocampus is crucial treatment target, the new chemical therapeutic agent, it is useful that the clinical trial of transvenous liposomal curcumin can confirm for PTSD.This be because, be exposed to the storage site that traumatic health or emotion event can be retained in the hippocampus and be associated in the brain as memory.This process can be regarded the part of survival mechanisms as, thereby so that adapt to the hostile event of recurrence, perhaps this process depends on the intensity of stimulation, the disturbance of neurotrophic factor, stress hormone epinephrine and norepinephrine, the hippocampus damage that the reduction of cortisol levels, Pathophysiology are induced.When on form and function when obstacle is arranged, may activate inherently or because extra input excites continuous response and recall uncontrollably " run away or fight " from the memory that stores responds.This can clinically can identify, and shows as the basic reason of the social pathology disease of memory distortion and PTSD.In cause not having recalling under the environmental stimuli phenomenon in event this mechanism can be owing to lack inhibition signal to superactivity hippocampus neurocyte.These are observed and point to hippocampus is the center element of PTSD.
For verify hippocampus in PTSD as target, be necessary to confirm that its clinical sign and symptom with PTSD is related when impaired, and when from treating when improving with acceptable safety responsibility generation benefit clinically.The evidence of target checking is from the diagnosing image of hippocampus Noninvasive, wherein under several neuropathic states, turn out to be size and reduce, and hippocampus pathology and symptom are relevant (the again generation (re-experiencing) of Traumatic Events are significant symptoms) at this moment.Here, the activity of effector is namely translated into the syndrome of unusual Spiritual Expression clinically through the hippocampus tissue of upsetting.Based on morphologic change, old and feeble rear neurocyte and the loss of neural stem cell and/or the sensation/physical damnification of hippocampus, this position is considered to estimate the first-selected target spot of pharmaceutical intervention.Limited pharmacology and test data about hippocampus neurocyte and neural stem cell supported disease model 4 based on the target regulation and control.This does not get rid of the modification to other target spots, described other target spots for example tonsil or produce reproducibility neurotrophic factor, degeneration stress hormone or, perhaps regulate the site of the receptor of these materials, the receptor of described these materials also can have contribution to PTSD.
It is polygenic obstacle that PTSD shows, and several gene stackings are namely arranged works.Different mice strain is different to the performance of frightened condition on the gene that keeps under the identical environment, and this has shown at this can have gene mutation in the model of simulated conditions (24)Following observed result has shown the relation between the genotype and lysis in the mankind, and the probability that the child that the Cambodia refugee child that father and mother suffer from PTSD does not suffer from PTSD than father and mother receives this diagnosis is high five times (25)In twin research, finding has effect gene in essence in community's sample of war experience and non-discharged soldier (26)In the research of PTSD, the positive correlation between dopamine transporter gene SLC6A33' polymorphism and the PTSD has been described in the most sane gene association (27)The latter's observed result can with liposomal curcumin at striatum, be positioned with that some are relevant in the dopaminergic neurocyte target (28)The inventor attempts in the key research of liposomal curcumin for patient's symptom, proves that by measuring useful effectiveness and safety hippocampus is effective target.Also have some facts to support that the hippocampus damage is the target that the liposomal curcumin treatment of the PTSD target of empirical tests and empirical tests is used: but the property of medicine (drugability) of target (i) emphasized through the concentration of liposomal curcumin behind the intravenously administrable in hippocampus (30)(ii) because; curcumin is crossed blood brain barrier; and for 6-OHDA toxicity protection rat striatum and black substance (Substantia Nigrum); but thereby set up the property of medicine chemically; and (iii) in order to limit the drug toxicity among the patient, determined the biomarker of erythrocyte liposomal curcumin toxicity, glutathion, thioredoxin reductase and annexin V and can be easy to monitoring.
Clinical trial: select curcumin be used for the PTSD clinical trial be based on its mechanism of action, its along the distribution of blood brain barrier with and in the distribution of striatum and hippocampus.The inventor has described new method, and the method is used transvenous liposomal curcumin in check EXPERIMENTAL DESIGN, and described EXPERIMENTAL DESIGN is based on I, II, III phase Clinical Project carries out.To be curcumin work as the inhibitor of progressivity disease and as the mitogen of neural stem cell the hypothesis of its effect.In this research, the other biological chemical change is monitored.And the level that reflects in hippocampus comprises the decline of 5-HT 1AmRNA in the cerebrospinal fluid of stress-induced and bdnf protein matter level.The II phase is tested specificity; Dosage regimen and treatment persistent period will be based on the I clinical trial phases.The scale of the research that the comparable III phase tests depends on the administration guide of amelioration of disease effect.In these trials, the inventor attempts measuring the biomarker of curcumin related activity, and the hippocampus neurodegeneration is carried out imaging with regenerating, and with this measurement result as output.Patient colony is by being comprised of patient with sympotoms of making a definite diagnosis, wherein for the patient n=300/ arm (arm) that is subject to PTSD and has a strong impact on.Inclusion criteria is set up according to behavioristics's standard sign of PTSD.
Curcumin is by inducing low sugar consumption, reduce serum cortex fat ketone, improving and improve chronic uncertain chronic stress (CUMS), the catalytic activity that improves adenosine cyclase (AC) and the level of cAMP in different brain regions, the mrna expression that raises AC hypotype AC2, AC8 and cAMP response element binding protein (CREB) in the hippocampus of hippocampus, cortex and CUMS rat improves chronic stress (CUMS).Its ultimate principle is as antidepressant (17)
Curcumin uses the memory ability that improves the Alzheimer mice incubation period (oral administration gives ALCL3 and gave the D-galactose 90 days through IP) of keeping away dark test (step-through test) and prolonging, and the apoptosis that inhibition is induced by A1C13 in PC 12 cells of cultivating.Mechanism table understands that BCL2 improves, and BAX (18)Do not improve.Curcumin has antioxidation in aging rats, the lipotropism class merges and the defying age effect (19)
The invention discloses progressive supranuclear plasy, Alzheimer, parkinson disease, Tau pathological changes and PTSD clinically the management in important improvement.Medicine passes blood brain barrier, locates in hippocampus and striatum, stops the neural cell injury of stress-induced, and excites the neural impaired neural circuit that forms and remedy.When using the chemotherapeutant of damage at the crucial neurocyte position be targeted to specifically as previously described stress-induced, the variation in the treatment example of AD, PD, PTSD and other neurocytes and neurodegenerative diseases can confirm for an open question it is more efficiently treatment.
Be contemplated that any embodiment of discussing in this description can be by implementing about any method of the present invention, test kit, reagent or compositions, vice versa.In addition, compositions of the present invention can be used for realizing method of the present invention.
It being understood that specific embodiments as herein described illustrates by way of example rather than limits method of the present invention shows.Principal character of the present invention can be used for various embodiments without departing from the present invention.Those skilled in the art will recognize that, perhaps only utilize conventional experiment can determine many equivalents of concrete steps described herein.Such equivalent is considered within the scope of the invention, and is contained by claim.
All publications of mentioning in this description and applications for patents understand technical staff that the invention relates to the field's level.All publication and patent applications all are incorporated herein by reference, and independently publication or patent application are concrete and be specified independently and be incorporated herein by reference as each for the degree of its introducing.
Word " one (a) " or " a kind of (an) " when with claim and/or description in term " comprise (comprising) " when being combined with, can refer to " a kind of ", but it is also consistent with " one or more ", " at least a " and " a kind of's or more than a kind of " the meaning.In the claims employed term " perhaps " refer to " and/or ", only refer to substitute unless clearly indicate, or substitute is mutually to repel, although the disclosure support only refer to substitute and " and/or " definition.In whole the application, term " approximately " is used for illustrating such value, and it comprises measuring the intrinsic variation of error of the apparatus and method of described value, perhaps studies the variation that exists between the experimenter.
As employed in this description and claim, word " comprises (comprising) " (and any type of " comprising ", such as " comprise (comprise) and comprise (comprises) "), " have (having) " (and any type of " having ", such as " having (have) " and " having (has) "), " comprise (including) " (and any type of " comprising ", such as " comprising (includes) " and " comprising (include) ") or " containing (containing) " (and any type of " containing ", such as " containing (contains) " and " containing (contain) ") be that comprise or open, and do not get rid of extra, the element of not addressing or method step.
Term as used herein " or their combination " refers to whole arrangements and the combination of cited project before this term.For example, " A, B, C or their combination " is intended to comprise at least a among A, B, C, AB, AC, BC or the ABC, and if in specific context order be important, so also comprise BA, CA, CB, CBA, BCA, ACB, BAC or CAB.Continue this example, what obviously comprise is the combination that comprises the repetition of one or more projects or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB etc.It will be appreciated by those skilled in the art that usually to the number of the project in any combination or term without limits, unless be obvious from the context in addition.
According to disclosure of the present invention, under inexcessive experiment, can prepare and implement disclosed herein and claimed whole compositionss and/or method.Although with the formal description of preferred embodiment the compositions and methods of the invention, but be apparent that to those skilled in the art, in the situation that does not break away from design of the present invention, spirit and scope, can change the order of the step of the step of compositions as herein described and/or method and method or method.Significantly all similar like this replacements and modification are considered to be in spirit of the present invention, scope and the design that appended claim limits to those skilled in the art.
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Claims (62)

1. one kind is used at experimenter's relief of symptoms and/or treats the compositions of one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination, and said composition comprises:
One or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in any in water or the nonaqueous solvent, and dissolving, is dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the described solvent;
The water that is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
2. compositions as claimed in claim 1, wherein said one or more neurological disorder or neurodegenerative diseases are selected from: progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease, alzheimer disease, vascular dementia, Pick's disease, Ke-Ya Shi are sick and old and feeble.
3. compositions as claimed in claim 1, wherein said one or more anxiety disorders comprise stress disorders, posttraumatic stress disorder (PTSD), phobia, psychic trauma or its combination.
4. compositions as claimed in claim 1; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
5. compositions as claimed in claim 1, wherein said compositions be suitable for through vein, through subcutaneous, through intramuscular or through the intraperitoneal administration.
6. compositions as claimed in claim 1, the size of wherein said one or more liposomees is about 100nm.
7. compositions as claimed in claim 1, wherein said compositions is through intravenously administrable.
8. one kind is used at experimenter's relief of symptoms and/or treats the compositions of one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination, and said composition comprises:
The Biodegradable polymeric conjugate, this conjugate dissolves or is dispersed in the suitable water or nonaqueous solvent, wherein said conjugate comprises the curcumin that is conjugated to one or more polymer, curcumin analogue, curcumin derivate or its combination, described polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, the polyalkylene oxalate, the polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination thereof or mixture; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
9. compositions as claimed in claim 8, wherein said one or more neurological disorder or neurodegenerative diseases are selected from: progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease, alzheimer disease, vascular dementia, Pick's disease, Ke-Ya Shi are sick and old and feeble.
10. compositions as claimed in claim 8, wherein said one or more anxiety disorders comprise stress disorders, posttraumatic stress disorder (PTSD), phobia, psychic trauma or its combination.
11. compositions as claimed in claim 8, wherein said compositions is through intravenously administrable.
12. compositions as claimed in claim 8, wherein said compositions are polylactic acid-glycollic acid (PLGA)-curcumin conjugates.
13. one kind is used at experimenter's relief of symptoms and/or treats the method for one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination, the method comprising the steps of:
Identification needs relief of symptoms and/or treats the experimenter of one or more neurodegenerative diseases, neurological disorder, anxiety disorder or its combination; With
Treat the pharmaceutical composition of (atherpeutically) effective dose through vein, described pharmaceutical composition comprises dissolving or is dispersed in suitable water or the curcumin in the non-aqueous media, curcumin analogue, curcumin derivate or its combination, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.
14. method as claimed in claim 13, the improvement of the step that also comprises the effect of the alleviation of monitoring symptom or neurodegenerative diseases, neurological disorder or both treatments, described monitoring memory, cognition, study, language, one or more motor skill or its combination by observing the experimenter is carried out.
15. method as claimed in claim 13 also comprises emotion by observing the experimenter or the change of behavior, monitors the effect of the treatment of the alleviation of symptom or anxiety disorder.
16. method as claimed in claim 13, wherein said liposome comprise lipid or phospholipid wall.
17. method as claimed in claim 16; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
18. method as claimed in claim 13, wherein said biodegradable polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, polyalkylene oxalate, polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination or mixture.
19. method as claimed in claim 13, wherein said pharmaceutical composition are polylactic acid-glycollic acid (PLGA)-curcumin conjugates.
20. method as claimed in claim 13, the size of wherein said one or more liposomees is about 100nm.
21. method as claimed in claim 13, wherein said treatment effective dose comprises experimenter's body weight of 50nM/kg.
22. method as claimed in claim 13, wherein said pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.
23. method as claimed in claim 22, wherein said pharmaceutically active agent comprises serotonin reuptake inhibitor, Sertraline and paroxetine.
24. a compositions that is used at experimenter's relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD), said composition comprises:
One or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin in water or the nonaqueous solvent, curcumin analogue, curcumin derivate or its combination, and dissolving, is dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the solvent;
The water that is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
25. compositions as claimed in claim 24; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
26. compositions as claimed in claim 24, the size of wherein said one or more liposomees is about 100nm.
27. compositions as claimed in claim 24, wherein said compositions is through intravenously administrable.
28. a compositions that is used at experimenter's relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD), said composition comprises:
The curcumin of puting together with biodegradable polylactic acid-glycollic acid (PLGA) copolymer, curcumin analogue, curcumin derivate, with and combination or trim, wherein said conjugate dissolving or be dispersed in the suitable water or nonaqueous solvent; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
29. compositions as claimed in claim 28, wherein said compositions is through intravenously administrable.
30. the method for relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD) in an experimenter, the method comprising the steps of:
Identification needs the experimenter of relief of symptoms and/or treatment progressive supranuclear plasy, Alzheimer (AD), parkinson disease (PD), Protein tau disease or posttraumatic stress disorder (PTSD); With
Treat the pharmaceutical composition of effective dose through vein, described pharmaceutical composition comprises the curcumin that wraps in one or more spherical liposomees or be conjugated to biodegradable polylactic acid-glycollic acid (PLGA) copolymer, curcumin analogue, curcumin derivate or its combination, wherein said liposome, described conjugate or both dissolvings or be dispersed in the medium of suitable water or non-water.
31. method as claimed in claim 30, also comprise the step of the effect of the alleviation of monitoring symptom or treatment, described monitoring is undertaken by the improvement of experimenter's memory, cognition, study, language, one or more motor skill, emotion, behavior or its combination.
32. method as claimed in claim 30, wherein said spherical liposome comprises lipid or phospholipid wall.
33. method as claimed in claim 32; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
34. method as claimed in claim 30, the size of wherein said one or more liposomees is about 100nm.
35. method as claimed in claim 30, wherein said treatment effective dose comprises experimenter's body weight of 50nM/kg.
36. method as claimed in claim 30, wherein said pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.
37. method as claimed in claim 36, wherein said one or more pharmaceutically active agents are selected from: serotonin reuptake inhibitor Sertraline, paroxetine, levodopa, carbidopa, benserazide, tolcapone, dopamine-receptor stimulant bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, MAO inhibitor, selegiline and rasagiline.
38. a compositions that is used at experimenter's relief of symptoms or treatment posttraumatic stress disorder (PTSD), said composition comprises:
Activating agent, described activating agent comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in water or the nonaqueous solvent, wherein said activating agent wraps in one or more spherical liposomees that comprise lipid or phospholipid wall, perhaps puts together with one or more biodegradable polymer;
Dissolve, be dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the solvent; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
39. compositions as claimed in claim 38, wherein said one or more spherical liposomees or described polymer conjugate can be dispersed in the disperse medium, and wherein said disperse medium is the disperse medium of water or non-water.
40. compositions as claimed in claim 38; wherein said lipid or phospholipid are selected from: phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
41. compositions as claimed in claim 38, wherein said one or more Biodegradable polymerics are selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, the polyalkylene oxalate, the polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination thereof or mixture.
42. compositions as claimed in claim 38, wherein said compositions through vein, through subcutaneous, through intramuscular or through the intraperitoneal administration.
43. compositions as claimed in claim 38, the size of wherein said one or more liposomees is about 100nm.
44. compositions as claimed in claim 38, wherein said compositions is through intravenously administrable.
45. one kind in the experimenter relief of symptoms or the treatment posttraumatic stress disorder (PTSD) method, the method comprising the steps of:
Identification needs the experimenter of relief of symptoms or PTSD; With
Treat the pharmaceutical composition of effective dose through vein, described pharmaceutical composition comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in the medium of suitable water or non-water, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.
46. method as claimed in claim 45 also comprises by observing the change of experimenter's emotion or behavior, monitors the effect of the treatment of the alleviation of symptom or PTSD.
47. method as claimed in claim 45; wherein said liposome comprises lipid or phospholipid wall; wherein said lipid or phospholipid are selected from: phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
48. method as claimed in claim 45, wherein said biodegradable polymer is selected from: polyester, polyactide, polyglycolide, polycaprolactone, polyanhydride, polyamide, polyurethane, polyesteramide, PPDO, polyacetals, polyketals, Merlon, poly-orthocarbonic ester, poe, poly phosphate, polyphosphazene, poly butyric ester, poly-hydroxyl valerate, polyalkylene oxalate, polyalkylene succinate, poly-(malic acid), poly-(aminoacid), copolymer, terpolymer and combination or mixture.
49. method as claimed in claim 45, the size of wherein said one or more liposomees is about 100nm.
50. method as claimed in claim 45, wherein said treatment effective dose comprises experimenter's body weight of 50nM/kg.
51. method as claimed in claim 45, wherein said pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.
52. method as claimed in claim 51, wherein said pharmaceutically active agent comprises serotonin reuptake inhibitor Sertraline and paroxetine.
53. a compositions that is used in experimenter's relief of symptoms or treatment parkinson disease (PD), said composition comprises:
One or more spherical liposomees, described spherical liposome comprises lipid or phospholipid wall, wherein said liposome is surrounded by dissolving or is dispersed in curcumin in water or the nonaqueous solvent, curcumin analogue, curcumin derivate or its combination, and dissolving, is dispersed or suspended in one or more optional relevant cofactor, protein, antibody, analgesic and other pharmaceutically active agents in the solvent;
The water that is fit to or the disperse medium of non-water, wherein said one or more spherical liposomees are dispersed in this disperse medium; With
Excipient, diluent, slow release or controlled release agent, lubricant, antiseptic or its combination in any that one or more are optional.
54. compositions as claimed in claim 53, the size of wherein said one or more liposomees is about 100nm.
55. compositions as claimed in claim 53, wherein said compositions is through intravenously administrable.
56. one kind in the experimenter relief of symptoms or the treatment parkinson disease (PD) method, the method comprising the steps of:
Identification needs the experimenter of relief of symptoms or treatment PD; With
Treat the pharmaceutical composition of effective dose through vein, described pharmaceutical composition comprises dissolving or is dispersed in curcumin, curcumin analogue, curcumin derivate or its combination in the medium of suitable water or non-water, wherein said curcumin wraps in one or more spherical liposomees, perhaps is conjugated to one or more Biodegradable polymerics.
57. method as claimed in claim 56, the change that also comprises language, one or more motor skill or other functions by observing the experimenter are monitored the step of effect of the treatment of the alleviation of symptom or PD.
58. method as claimed in claim 56; wherein said liposome comprises lipid or phospholipid wall; wherein said lipid or phospholipid are selected from phosphatidylcholine (lecithin); LYSOLECITHIN SUNLECITHIN A; lysophosphatidyl ethanolamine; Phosphatidylserine; phosphatidylinositols; sphingomyelins; PHOSPHATIDYL ETHANOLAMINE (cephalin); cuorin; phosphatidic acid; cerebroside; DCP; phosphatidylcholine, and DPPG; stearylamine; lauryl amine; hexadecylamine; the acetyl group cetylate; the glycerol ricinoleate; the stearic acid cetyl; isopropyl myristate; the acrylic polymer of both sexes; fatty acid; fatty acid amide; cholesterol; cholesteryl ester; diglyceride and diacylglycerol succinate.
59. method as claimed in claim 56, the size of wherein said one or more liposomees is about 100nm.
60. method as claimed in claim 56, wherein said treatment effective dose comprises experimenter's body weight of 50nM/kg.
61. method as claimed in claim 56, wherein said pharmaceutical composition randomly with relevant cofactor, protein, antibody, analgesic and the together administration of other pharmaceutically active agents.
62. method as claimed in claim 61, wherein said one or more pharmaceutically active agents are selected from: levodopa, carbidopa, benserazide, tolcapone, dopamine-receptor stimulant bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, MAO inhibitor, selegiline and rasagiline.
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